Tau-containing neuronal inclusions are a prominent feature of Alzheimer?s disease (AD), frontal temporal dementia (FTD) and other disorders with tauopathy, implying a deficit in the cell?s ability to clear misfolded tau species either as a cause or a consequence of the disease process. Tau is a substrate of the ubiquitin proteasome system (UPS), thus elucidating mechanisms how proteasome becomes dysfunctional in tauopathy may identify pathways that could be targeted therapeutically. Synaptic dysfunction, which is thought to be an early pathological manifestation in AD and other tauopathies, is associated with abnormal missorting and accumulation of tau in synapses. And recent evidence suggests that pathogenic progression in synapses in AD correlates with accumulation of ubiquitinated proteins in synaptic fractions, suggesting UPS dysfunction. Here we propose that missorted tau in synapses disrupts proteasomal activity contributing to broader synaptic toxicity. We hypothesize that one of the consequences of tau-induced impaired synaptic proteolysis is sustained tetrameric (inactive) conformation of PKA holoenzyme and downregulation of CREB transcription signaling, an important pathway related to synaptic plasticity and memory. The goal of AIM 1 is to examine whether there is a relationship between accumulation of pathological tau in pre and post -synaptic compartments, the function of synaptic proteolysis and the status of PKA/CREB signaling using brain tissue from AD, FTD and normal brains. Examination of the synaptic distribution of tau species in the pre and post synaptic compartment and its competency to seed and propagate will enable us to identify the biochemical signature of synaptic tau in two tauopathies. In an effort to identify mechanisms that contribute to synaptic toxicity, AIM 2 will test in a series of in vitro assays using primary neurons and microfluidic-based cell model of fluidically isolated synapses, whether accumulation of tau aggregates throughout the cell or in synapses (during trans-synaptic propagation), can elicit a negative effect on the PKA/CREB signaling due to impaired proteasome clearance mechanism. As a therapeutic strategy, AIM 3 will investigate if stimulation of Gs-coupled GPCR, situated on the synaptic terminals, rescues/activates cAMP/PKA pathway leading to increased proteasome proteolysis of tau species in synapses. The application of a therapeutic strategy of receptor- stimulated proteolysis with spatially defined mechanism of action for effective tau clearance, can identify a new mechanism to halt missorting of tau and subsequent trans-synaptic spread. Targeting GPCR signaling as a strategy to activate proteasome mediated proteolysis can have a significant impact in finding new drugs for proteinopathy diseases.